The present invention relates to compositions which inhibit replication of herpes virus and the bacterium Neisseria gonorrheae, and methods of using such compositions to treat subjects infected with these microorganisms.
Human herpes viruses can infect host cells in virtually any organ of the human body. Replication of a herpes virus within an infected host cell leads to lysis of the infected cell and the release of large numbers of infectious virus. The infectious particles released from the lysed cell can infect and destroy other cells at or near the site of the initial infection. These infectious particles can also be transmitted to a non-infected individual. Human herpes viruses can also enter and remain latent, i.e., in the non-replicative state, in other cells of the afflicted individual for life. This life-long infection serves as a reservoir of infectious virus for recurrent infections in the afflicted individual and as a source of infection for an unwitting contact.
At least four of the human herpes viruses, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), and varicella zoster virus (VZV) are known to infect and cause lesions in the eye of certain infected individuals. Together, these four viruses are the leading cause of infectious blindness in the developed world.
HSV-1 primarily infects the oral cavity, while HSV-2 primarily infects genital sites. However, any area of the body, including the eye, skin and brain, can be infected with either type of HSV. Generally, HSV is transmitted to a non-infected individual by direct contact with the infected site of the infected individual.
The initial symptoms of a primary or recurrent HSV infection include tingling, pain, and/or parasthesia at the site of infection. This is followed by formation of a lesion at the infected site, i.e., in the oral cavity, eye, skin, or reproductive tract. Healing typically occurs in approximately ten to fourteen days.
The immune reaction that occurs in response to an HSV infection prevents dissemination of the virus throughout the body of the immmunocompetent individual. Such immune reaction, however, does not eliminate all infectious HSV particles from the body of the afflicted individual. The virus particles that are not killed by the immune response move along the nerve path to the ganglia of the infected individual where they remain in a state of latency. In response to a variety of stimuli including stress, environmental factors, other medications, food additives or food substances, the infectious virus particles may leave the ganglia and cause a recurrent infection at or near the original site of infection. In those HSV-infected individuals who are immunosuppressed or who lack a well-developed immune system, such as neonates, dissemination of the virus particles from the infected site can also occur and lead to life-threatening complications, including encephalitis.
VZV, which is transmitted by the respiratory route, is the cause of chickenpox, a disease which is characterized by a maculopapular rash on the skin of the infected individual. As the clinical infection resolves, the virus enters a state of latency in the ganglia, only to reoccur in some individuals as herpes zoster or xe2x80x9cshinglesxe2x80x9d. The reoccurring skin lesions remain closely associated with the dermatome, causing intense pain and itching in the afflicted individual.
CMV is more ubiquitous and may be transmitted in bodily fluids. The exact site of latency of CMV has not been precisely identified, but is thought to be leukocytes of the infected host. Although CMV does not cause vesicular lesions, it does cause a rash.
There are no known cures for infections with human herpes viruses, i.e., methods of eliminating the virus from the body of the infected individual. In addition, there are very few methods for blocking the formation of infectious herpes virus particles and thereby reducing the frequency, severity, or duration of a herpes virus-induced infection and the likelihood of recurrence of infection in the latently-infected individual. Thus, it is desirable to have additional methods for inhibiting the formation of infectious herpes virus particles. Such method is useful for limiting the severity of a herpes virus infection within an infected individual and the likelihood of transmission of the herpes virus infection from the infected individual to a non-infected individual.
Neisseria gonorrhea is a gram negative bacterium that is pathogenic in humans. The bacterium is spread from person to person by contact with infected secretions, most often by sexual contact. Once the pathogen is deposited on a mucosal surface, a complex series of molecular interactions occur that result in invasion of mucosal columnar cells. The spectrum of diseases ranges from local infections of the urethral, cervical, rectal and oropharyngeal membranes to invasion of the pelvis or epididymis, to invasion of the blood stream, with or without dissemination to distant organs such as heart valves, joints, and pericardium. The pathogen may also infect the conjunctiva. Gonococcal conjunctivitis is most often contracted by neonates passing through an infected birth canal, although adults can also be infected.
The quest for a gonococcal vaccine has been ongoing for many years with virtually no success. Accordingly, the primary treatment involves preexposure or postexposure antibiotic prophylaxis. In addition to antibiotic eyedrops, silver nitrate has also been used to treat neonatal gonococcal conjunctivitis. Unfortunately, the bacterium has developed resistance to some of the most common antibiotics, such as penicillin. Accordingly, additional compositions for reducing growth of this pathogen are desirable.
The present invention provides a new method of inhibiting the formation of infectious herpes virus particles, particularly infectious HSV particles, in a host cell. The method involves administering a hydroxylated tolan, particularly dihydroxytolan or trihydroxytolan, to a herpes virus infected host cell. The hydroxylated tolan is administered to the host cell in an amount sufficient to inhibit replication of the virus in the virus-infected host cell. Such method is useful for reducing the cytopathic effect of a herpes virus infection. Such method is also useful for preventing the spread of the herpes virus from a virus-infected host cell to a non-infected host cell. Such method is also useful for establishing a model system for studying the molecular events that occur during replication of herpes virus and for studying the factors that trigger replication of a latent herpes virus, particularly replication of latent HSV.
The present invention also provides a method of treating a subject having or suspected of having a herpes virus infection, particularly an HSV infection. The method comprises administering a topical composition comprising a therapeutically effective amount of a hydroxylated tolan, particularly a di-hydroxylated or tri-hydroxylated tolan, to a herpes virus-infected site. The present invention also relates to a topical composition for treating a herpes virus infection selected from the group consisting of an HSV infection, a CMV infection, and a VZV infection.
The present invention also provides a method of inhibiting replication of the gram negative bacterium Neisseria gonorrhea. Such method involves contacting the bacterium with a composition containing a hydroxylated tolan, preferably a di-hydroxylated or tri-hydroxylated tolan. In vivo, such method can be used to treat an individual who has come in contact with, (e.g., a carrier), or an individual who is expected to come into contact with the bacterium. In vivo, such method comprises administering a composition comprising a therapeutically effective amount of a hydroxylated tolan, particularly a tri-hydroxylated tolan to the subject